Insights on Comorbidities and Narcolepsy Treatment From World Sleep Congress 2025

WATCH TIME: 9 minutes | Captions are auto-generated and may contain errors.

Once-nightly oxybate (Lumyrz; Avadel Pharmaceuticals), initially approved in 2023 for adults with narcolepsy to treat excessive daytime sleepiness and cataplexy, had its indication expanded in late 2024 to include patients aged 7 years and older.^1,2 Researchers presented new findings from the multicenter observational REFRESH study, assessing the efficacy, satisfaction, and safety of once-nightly sodium oxybate, at the 2025 World Sleep Congress, held September 5-10, in Singapore.³

The goal of REFRESH is to understand more about the real-world experiences with once-nightly sodium oxybate, as well as gain insights for decision-making between twice-nightly and once-nightly solutions. Recently, NeurologyLive^® held a roundtable discussion with 2 sleep experts who talked about the real-world data from the REFRESH study presented at the Congress. Panelists in this conversation included Gerard J. Meskill, MD, the founder and CEO of Tricoastal Narcolepsy and Sleep Disorders Center in Sugar Land, Texas, and Laura B. Herpel, MD, a sleep physician at Bogan Sleep Consultants in Columbia, South Carolina.

In this second episode, Meskill and Herpel discussed the complex landscape of comorbidities in patients with narcolepsy. The duo highlighted real-world data from REFRESH, showing increased odds of these conditions in individuals with narcolepsy. Both emphasized that therapies like oxybate not only improve disrupted nocturnal sleep but can also positively impact daytime function, cognitive clarity, and comorbid psychiatric symptoms. Experts noted the importance of recognizing and addressing these comorbidities to reduce misdiagnosis and improve overall patient outcomes.

Transcript edited for clarity. Click here to view more of our coverage on sleep disorders.

Isabella Ciccone, MPH: Another question that I have is, were there any data that touched upon comorbidities in terms of narcolepsy? I mean, we touched a little bit on quality of life but I was wondering if you had any other insights on that.

Gerard J. Meskill, MD: I don't know about looking at specific data on comorbidities, but rather just discussion of comorbidities in general. With narcolepsy, there are data points on the percentage of people with narcolepsy who also have incidents of depression, for instance. And whatever that number is, it's too low, because it seems to me like it's practically 100%. These folks, on average, will go almost 10 years and see multiple different clinicians from time of onset of symptoms until diagnosis, which means lots of mislabels, lots of failed treatments.

And remember, the peak age of onset for this disease is between 15 to 25 years, often during pediatric and teenage years. That 15-to-25-year period—that's where you apply for college. That's where you try to figure out what you're going to do with your life. For a lot of people, that's where they start potentially meeting their significant other and trying to start a family. These are high real estate years in a person's life to be terribly, terribly sleepy and, despite seeking help, finding no answers. So the way I look at it is, treating narcolepsy in many instances improves quality of life, improves mood, improves depression, improves anxiety. I don't think that can be understated.

Laura B. Herpel, MD: And I agree completely. We see patients in our office all the time that have significant comorbidities that are quite common. I think there was some data presented as well at the 2025 World Sleep Congress that had shown some of the, again, real-world data looking at EHR analyses with Duke. The Duke study had shown significant odds of having depression and anxiety, as well as ADHD, in individuals with narcolepsy. Now, the question is, chicken or the egg, right? What comes first? But these patients had higher odds ratios of having ADHD and PTSD, which surprised me. Anxiety and depression odds ratios have ranged anywhere between 1.8 for anxiety and 2.7 for depression. So that was pretty interesting.

The chronic pain syndromes, and we see this a lot—fibromyalgia and chronic fatigue syndrome—we see these a lot in our clinic population. They also saw increased POTS, which I am seeing more and more of nowadays. Whether or not we have better diagnostics for that, I think people are recognizing it more, but I think there's some autonomic dysfunction that we see associated with narcolepsy, so higher POTS odds in patients who have narcolepsy.

What's interesting is, we all worry about using these medications in patients with anxiety and depression, but time and time again—and I'm cautious, because it's a serious medication, it can have some serious adverse effects, and we're very cautious in these patients—but time and time again, I have used oxybates for my patients and seen anxiety and depression improve. I mean, I have to watch out, because there are those that definitely have adverse effects and can get worse. But even the REFRESH data that was out there showed patient-reported symptoms of anxiety and patient-reported symptoms of depression both improved in patients who were switching and patients who were not switching.

And what's interesting is, a lot of other things, like brain fog and mental clarity, those abilities to focus, they all went in the positive direction. I think it's really interesting to see how, if you're extrapolating that data from a comorbidity, perhaps the comorbidities of ADHD improve. Is it possible that these oxybates—not only are they impacting the quality of sleep, for sure, the disrupted nocturnal sleep, the REM dissociative events that occur, the hypnagogic hallucinations, hypnopompic hallucinations, the sleep paralysis—but really balancing that sleep-wake switch. So, patients have more solid sleep, regulating wakefulness much better, improving their daytime fatigue and sleepiness, and improving some of these other symptoms that go along with or are exacerbated by daytime sleepiness? Maybe we should say so. It was nice to see that data corresponding. There's a lot more possibility of having these disorders, but treating patients appropriately may actually help them a bit.

Gerard J. Meskill, MD: Well, I think that's a wealth of great points, but I'm going to focus on a couple of them that you made, Herpel. When we treat disease, if possible, we want to cure the underlying condition, which at this stage in time, we can't do with narcolepsy. Who knows in the future? But if you can't, then you want to try to get at the underlying cause of the condition as much as possible. I think we'd agree that, in its essence, narcolepsy is a disorder of profoundly disrupted sleep with intrusion of abnormal sleep architecture during the day.

It's interesting that an agent like oxybate, which in essence has a half-life of about 60 minutes, now with the once-nightly immediate and extended-release combined, can be spread out over the course of the night. But how it has these far-reaching effects on daytime function as well speaks to the fact that we're improving sleep continuity, improving the depth of sleep, and reducing phase shifting during the night.

The DUET studies showed that with oxybate, even though the actual bioavailability is during the nighttime hours, it's leading to improved daytime function as well. Because narcolepsy is a 24-hour-a-day disease, all that you're pointing out demonstrates that rather than just trying to treat symptoms, which can be important too, but giving a medication that for a few hours makes somebody feel more awake without addressing the fact that their sleep is fundamentally damaged is not going to be as close to getting to the pathology as actually being able to improve the depth and continuity of sleep.

You also mentioned seeing more and more dysautonomia with narcolepsy. We are too. Two years ago, for the National Sleep meeting, we presented data from our clinic. We looked at what percentage of our patients with narcolepsy had been found to have confirmed POTS, just like you said. We found that type 1 was 18%, which is 25 times the national average or something like that. Even type 2, it was about 4%, so we're seeing substantially higher rates of confirmed POTS in narcolepsy compared with the overall population. There does seem to be an autonomic function deficiency underlying narcolepsy. We've also been seeing more and more association with Ehlers-Danlos Syndrome and with mast cell activation syndrome. It's interesting developments, as we learn more about narcolepsy and its associated disease states, that there do seem to be certain tie-ins.

Laura B. Herpel, MD: I agree, and I often wonder if those comorbidities are possibly contributing to some of the misdiagnosis or delay in diagnosis as well. Technically, narcolepsy can start as early as 7 years old. It can start much earlier in life. We don't see it as often, but maybe we're missing it. Maybe it's getting diagnosed as ADD instead, and we're catching it later down the road when treating ADD is not helping.

Gerard J. Meskill, MD: Or its actually is distracting this, of course. How do you treat ADD? Typically with stimulants, which can increase sleepiness. I agree with you, 100%.

REFERENCES
1. Avadel Pharmaceuticals announces final FDA approval of Lumryz (sodium oxybate) for extended-release oral suspension as the first and only once-at-bedtime oxybate for cataplexy or excessive daytime sleepiness in adults with narcolepsy. News release. Avadel Pharmaceuticals. May 1, 2023. Accessed November 5, 2025. https://www.globenewswire.com/news-release/2023/05/01/2658536/0/en/Avadel-Pharmaceuticals-Announces-Final-FDA-Approval-of-LUMRYZ-sodium-oxybate-
2. Avadel Pharmaceuticals Announces FDA Approval of LUMRYZ™ (sodium oxybate) Extended-Release Oral Suspension (CIII) for the Treatment of Cataplexy or Excessive Daytime Sleepiness in Patients 7 Years of Age and Older with Narcolepsy. News Release. Avadel Pharmaceuticals. Published October 17, 2024. Accessed November 5, 2025. https://investors.avadel.com/news-releases/news-release-details/avadel-pharmaceuticals-announces-fda-approval-lumryztm-sodium
3. Avadel Pharmaceuticals to Present New Data on LUMRYZ™ (sodium oxybate) for Extended-Release Oral Suspension at World Sleep 2025. News release. Avadel Pharmaceuticals. September 5, 2025. Accessed November 5, 2025. https://investors.avadel.com/news-releases/news-release-details/avadel-pharmaceuticals-present-new-data-lumryztm-sodium-0